Minimal residual disease (MRD) contaminating the stem cell source and chemo-radiotherapy resistant MRD in the multiple myeloma (MM) patient (pt) contribute to relapse following myeloablative therapy. Project 2 proposes to develop novel strategies to eradicate MRD in MM. To eradicate MRD contaminating the stem cell source, we propose to develop techniques that will purge all MM cells that can be detected by PCR. In an attempt to treat MRD within the pt, we propose to develop adoptive T cell therapy that will eradicate PCR detectable disease. To achieve these goals, we propose to undertake the basic laboratory experiments, pre-clinical studies and scale up, and clinical trials necessary to address these issues. The central hypothesis of this proposal is that human MM antigens (Ag) exist; however, due to immunosuppression in the tumor bearing host and/or ineffective Ag presentation, no clinically significant anti-MM T cell response is generated. B cell neoplasms are themselves extremely poor Ag presenting cells (APC). However, malignant B cells modified in vitro by CD40 activation become very potent APCs and can be used to ex vivo T cell stimulation of tumor-specific T cells. We have also been able to generate large numbers of normal CD40 activated B cells that can be leaded with tumor Ag and can be used ex vivo to generate autologous T cells specifically recognizing Ag on tumor cells. Preliminary evidence demonstrates that we can improve the APC capacity of MM cells to be used as stimulators for ex vivo T cell expansion. We plan to extend these observations to induce and optimize anti-MM specific T cell immunity and to translate these observation to the clinical area. We propose four Aims. First, we plan to develop technologies to purge the stem cell of contaminating MM cells and demonstrate the superiority of this product. Second, we plan to determine the T cell immunocompetence of the MM patient prior to treatment, following conventional therapy, and after myeloablative therapy. Third, we plan to develop methods to generate and expand anti-MM specific autologous T cells ex vivo and undertake clinical scale up. Finally, we plan to undertake clinical trials to adoptively transfer anti-MM specific autologous T cells to treat MRD in MM patients following myeloablative therapy. Project 2 relies upon and his highly interdependent with Project 1 (developing allogeneic MM specific immunity) and with Project 3 (vaccines to induce autologous MM specific T cell ex vivo). Critical to the success of Project 2 is Core B and C which will provide MRD detection and immune assessment.